Levodopa responsive asymmetric parkinsonism as clinical presentation of progranulin gene mutation.

Early diagnosis of neurodegenerative diseases is a challenge that we must face given the increasing emergence of promising treatments tackling the molecular mechanisms underlying each specific neurodegenerative form. Progranulin (GRN) gene mutations were discovered in families with frontotemporal dementia (FTD) in 2006 [ [1] Baker M. Mackenzie I.R. Pickering-Brown S.M. Gass J. Rademakers R. Lindholm C. Snowden J. Adamson J. Sadovnick A.D. Rollinson S. Cannon A. Dwosh E. Neary D. Melquist S. Richardson A. Dickson D. Berger Z. Eriksen J. Robinson T. Hutton M. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006; 442: 916-919https://doi.org/10.1038/nature05016 Crossref PubMed Scopus (1631) Google Scholar ]. Since then, about 130 mutations linked with FTD have been reported. Frameshift and nonsense mutations are the most common pathogenic variants, inserting premature stop codons that lead to mRNA degradation and haploinsufficiency [ [6] Kleinberger G. Capell A. Haass C. Van Broeckhoven C. Mechanisms of granulin deficiency: lessons from cellular and animal models. Mol. Neurobiol. 2013; 47: 337-360https://doi.org/10.1007/s12035-012-8380-8 Crossref Scopus (47) Google Scholar ]. Heterozygous GRN mutations are responsible for about one third of autosomal dominant FTD cases worldwide [ [14] Terryn J. Verfaillie C.M. van Damme P. Tweaking progranulin expression: Therapeutic avenues and opportunities. in: Frontiers in Molecular Neuroscience. vol. 14. Frontiers Media S.A, 2021https://doi.org/10.3389/fnmol.2021.713031 Crossref Scopus (15) Google Scholar ]. The phenotypic spectrum is quite heterogeneous [ [7] le Ber I. Camuzat A. Hannequin D. Pasquier F. Guedj E. Rovelet-Lecrux A. Hahn-Barma V. van der Zee J. Clot F. Bakchine S. Puel M. Ghanim M. Lacomblez L. Mikol J. Deramecourt V. Lejeune P. de La Sayette V. Belliard S. Vercelletto M. Camu W. Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study. Brain. 2008; 131: 732-746https://doi.org/10.1093/brain/awn012 Crossref PubMed Scopus (287) Google Scholar , [15] van Swieten J.C. Heutink P. Rapid Review Mutations in Progranulin (GRN) within the Spectrum of Clinical and Pathological Phenotypes of Frontotemporal Dementia. 965. 2008https://doi.org/10.1016/S1474 Crossref Google Scholar ]. Extrapyramidal symptoms can be observed over the course of the disease, but very rarely they may precede cognitive disturbances profiling into an atypical parkinsonism or a phenotype similar to Parkinson's disease (PD) [ [12] Seelaar H. Rohrer J.D. Pijnenburg Y.A.L. Fox N.C. van Swieten J.C. Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J. Neurol. Neurosurg. Psychiatry. 2011; 82 (BMJ Publishing Group): 476-486https://doi.org/10.1136/jnnp.2010.212225 Crossref PubMed Scopus (435) Google Scholar ].